The present invention relates to bicyclic derivatives, their synthesis and their use, for example, for the treatment of disorders and conditions mediated by the histamine receptor.
Histamine [2-(imidazol-4-yl)ethylamine] is a transmitter substance. Histamine exerts a physiological effect via multiple distinct G-protein coupled receptors. It plays a role in immediate hypersensitivity reactions and is released from mast cells following antigen IgE antibody interaction. The actions of released histamine on the vasculature and smooth muscle system account for the symptoms of the allergic response. These actions occur at the H1 receptor (Ash, A. S. F. and Schild, H. O., Br. J. Pharmacol., 1966, 27, 427) and are blocked by the classical antihistamines (e.g. diphenhydramine). Histamine is also an important regulator of gastric acid secretion through its action on parietal cells. These effects of histamine are mediated via the H2 receptor (Black, J. W., Duncan, W. A. M., Durant, C. J., Ganellin, C. R. and Parsons, E. M., Nature, 1972, 236, 385) and are blocked by H2 receptor antagonists (e.g. cimetidine). The third histamine receptorxe2x80x94H3xe2x80x94was first described as a presynaptic autoreceptor in the central nervous system (CNS) (Arrang, J.-M., Garbarg, M., and Schwartz, J.-C., Nature 1983, 302, 832) controlling the synthesis and release of histamine. Recent evidence has emerged showing that the H3 receptors are also located presynaptically as heteroreceptors on serotonergic, noradrenergic, dopaminergic, cholinergic, and GABAergic (gamma-aminobutyric acid containing) neurons. These H3 receptors have also recently been identified in peripheral tissues such as vascular smooth muscle. Consequently there are many potential therapeutic applications for histamine H3 agonists, antagonists, and inverse agonists. (See: xe2x80x9cThe Histamine H3 Receptor-A Target for New Drugsxe2x80x9d, Leurs, R., and Timmerman, H., (Editors), Elsevier, 1998; Morisset et al., Nature, 2000, 408, 860-864.) A fourth histamine receptorxe2x80x94H4xe2x80x94was recently described by Oda et al., (J. Biol. Chem., 2000, 275, 36781-36786).
The potential use of histamine H3 agonists in sleep/wake and arousal/vigilance disorders is suggested based on animal studies (Lin et al, Br. Res., 1990, 523, 325; Monti et al Eur. J. Pharmacol., 1991, 205, 283). Their use in the treatment of migraine has also been suggested (McLeod et al Abstr. Society Neuroscience, 1996, 22, 2010) based on their ability to inhibit neurogenic inflammation. Other applications could be a protective role in myocardial ischemia and hypertension where blockade of norepinephrine release is beneficial (Imamura et al J. Pharmacol. Expt. Ther., 1994, 271,1259). It has been suggested that histamine H3 agonists may be beneficial in asthma due to their ability to reduce non-adrenergic non-cholinergic (NANC) neurotransmission in airways and to reduce microvascular leakage (Ichinose et al Eur. J. Pharmacol., 1989,174, 49).
Several indications for histamine H3 antagonists and inverse agonists have similarly been proposed based on animal pharmacology experiments with known histamine H3 antagonists (e.g. thioperamide). These include dementia, Alzheimer""s disease (Panula et al Abstr. Society Neuroscience, 1995, 21,1977), epilepsy (Yokoyama et al Eur. J. Pharmacol., 1993, 234,129) narcolepsy, eating disorders (Machidori et al Brain Research 1992, 590,180), motion sickness, vertigo, attention deficit hyperactivity disorders (ADHD), learning and memory (Barnes et al Abstr. Society Neuroscience, 1993,19,1813), schizophrenia (Schlicker et al Naunyn-Schmiedeberg""s Arch. Pharmacol., 1996, 353, 290-294); (also see; Stark et al Drugs Future, 1996, 21, 507 and Leurs et al Progress in Drug Research, 1995, 45, 107 and references cited therein). Histamine H3 antagonists, alone or in combination with a histamine H1 antagonist, are reported to be useful for the treatment of upper airway allergic response (U.S. Pat. Nos. 5,217,986; 5,352,707 and 5,869,479). Recently, a histamine H3 antagonist (GT-2331) was identified and is being developed by Gliatech Inc. (Gliatech Inc. Press Release Nov. 5,1998; Bioworld Today, Mar. 2,1999) for the treatment of CNS disorders.
As noted, the prior art related to histamine H3 ligands has been comprehensively reviewed (xe2x80x9cThe Histamine H3 Receptor-A Target for New Drugsxe2x80x9d, Leurs, R., and Timmerman, H., (Editors), Elsevier, 1998). Within this reference the medicinal chemistry of histamine H3 agonists and antagonists was reviewed (see Krause et al and Phillips et al respectively). The importance of an imidazole moiety containing only a single substitution in the 4 position was noted together with the deleterious effects of additional substitution on activity. Particularly methylation of the imidazole ring at any of the remaining unsubstituted positions was reported to strongly decrease activity. Additional publications support the hypothesis that an imidazole function is essential for high affinity histamine H3 receptor ligands (See, Ali et al J. Med. Chem., 1999, 42, 903 and Stark et al, Drugs Future, 1996, 21, 507 and references cited therein). However many imidazole containing compounds are substrates for histamine methyl transferase, the major histamine metabolizing enzyme in humans, which leads to shortened half lives and lower bioavailability (See, Rouleau et al J. Pharmacol. Exp. Ther. 1997, 281,1085). In addition, imidazole containing drugs, via their interaction with the cytochrome P450 monooxygenase system, can result in unfavorable biotransformations due to enzyme induction or enzyme inhibition. (Kapetanovic et al Drug Metab. Dispos. 1984,12, 560; Sheets et al Drug Metab. Dispos. 1984,12, 603; Back, et al Br. J. Pharmacol. 1985, 85,121; Lavrijsen et al Biochem. Pharmacol. 1986, 35, 1867; Drug Saf., 1998, 18, 83). The poor blood brain barrier penetration of earlier histamine H3 receptor ligands may also be associated with the imidazole fragment (Ganellin et al Arch. Pharm. (Weinheim,Ger.) 1998, 331, 395).
More recently, several publications have described histamine H3 ligands that do not contain an imidazole moiety. For example; Ganellin et al Arch. Pharm. (Weinheim,Ger.) 1998, 331, 395; Walczynski et al Arch. Pharm. (Weinheim,Ger.) 1999, 332, 389; Walczynski et al Farmaco 1999, 684; Linney et al J. Med. Chem. 2000, 2362; Tozer and Kalindjian Exp. Opin. Ther. Patents 2000,10,1045-1055; U.S. Pat. No. 5,352,707; PCT Application W099/42458, Aug. 26,1999; and European Patent Application 0978512, Feb. 9, 2000.
The compounds of the present invention do not contain the imidazole moiety, and its inherent liabilities, and maintain potency at the human H3 receptor. Thus in the present invention receptor binding was determined using the human histamine H3 receptor (See Lovenberg et al Mol. Pharmacol. 1999, 1107). Screening using the human receptor is particularly important for the identification of new therapies for the treatment of human disease. Conventional binding assays for example are determined using rat synaptosomes (Garbarg et al J. Pharmacol. Exp. Ther. 1992, 263, 304), rat cortical membranes (West et al Mol. Pharmacol. 1990, 610), and guinea pig brain (Korte et al Biochem. Biophys. Res. Commun. 1990, 978). Only limited studies have been performed previously using human tissue but these allude to significant differences in the pharmacology of rodent and primate receptors (West et al Eur. J. Pharmacol. 1999, 233).
We now describe a series of bicyclic derivatives with the ability to modulate the activity of the histamine receptor, specifically the H3 receptor, without the inherent problems associated with the presence of an imidazolyl moiety.
The present invention is directed to a compound of formula (I): 
wherein each of W1 and W2 is H;
X1 is selected from Ga, RaGa, LaGa, and RaLaGa;
X2 is selected from Gb, RbGb, LbGb, and RbLbGb;
each of Ga and Gb is independently NR3aR4a or NR3bR4b, respectively, or pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, isoindolinyl, morpholinyl, piperazinyl, imidazolyl, thiazolinyl, 5,6-dihydro-3-imidazo[2,1-B]thiazolyl, or thiazolyl; wherein each of R3a, R4a, R3b and R4b is independently selected from H, C1-8 alkyl, C3-7 cycloalkyl, and (C3-7 cycloalkyl)C1-6 alkyl;
Gb can be further selected from nitro, halo, OH, CHO, pyrrolyl, or xe2x88x92C(=NOH)H;
each of Ra and Rb is independently O, S, NH or C=O;
each of La and Lb is independently C1-3 alkylene;
Y is a covalent bond where one of Z1 and Z2 is N, O, or S; Y can also be SO2, C=O, CH2, CH2CH2, OCH2, CH2O, or NRC, wherein Rc is H, C1-8 alkyl, C3-7 cycloalkyl, (C3-7 cycloalkyl)C1-6 alkyl, C2-5 heterocyclyl, (C2-7 heterocyclyl)C1-6 alkyl, phenyl, (phenyl)C1-6 alkyl, or [di (C1-6 alkyl)amino]C1-6 alkyl;
each of Z1 and Z2 is independently N, O, S, or xe2x80x94CHxe2x95x90CHxe2x80x94 to form a phenyl ring;
or a pharmaceutically acceptable salt, amide or ester thereof.
The invention also features a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier; and methods of preparing or formulating such compositions. A composition of the invention may further include more than one compound of the invention, or a combination therapy (combination formulation or administering a combination of differently formulated active agents).
The invention also provides methods of treating certain conditions and diseases, each of which methods includes administering a therapeutically effective (or jointly effective) amount of a compound or composition of the invention to a subject in need of such treatment. The disclosed compounds are useful in methods for treating or preventing neurologic disorders including sleep/wake and arousal/vigilance disorders (e.g. insomnia and jet lag), attention deficit hyperactivity disorders (ADHD), learning and memory disorders, cognitive dysfunction, migraine, neurogenic inflammation, dementia, mild cognitive impairment (pre-dementia), Alzheimer""s disease, epilepsy, narcolepsy, eating disorders, obesity, motion sickness, vertigo, schizophrenia, substance abuse, bipolar disorders, manic disorders and depression, as well as other histamine H3 receptor mediated disorders such as upper airway allergic response, asthma, itch, nasal congestion and allergic rhinitis in a subject in need thereof. For example, the invention features methods for preventing, inhibiting the progression of, or treating upper airway allergic response, asthma, itch, nasal congestion and allergic rhinitis.
In yet another embodiment, the disclosed compounds may be used in a combination therapy method including administering a jointly effective dose of an H3 antagonist and administering a jointly effective dose of a histamine H1 antagonist, such as loratidine (CLARITIN(trademark)), desloratidine (CLARINEX(trademark)), fexofenadine (ALLEGRA(trademark)) and cetirizine (ZYRTEC(trademark)), for the treatment of allergic rhinitis, nasal congestion, and allergic congestion.
In yet another embodiment, the disclosed compounds may be used in a combination therapy method, including administering a jointly effective dose of an H3 antagonist and administering a jointly effective dose of a neurotransmitter re-uptake blocker, such as a selective serotonin re-uptake inhibitor (SSRI) or a non-selective serotonin, dopamine or norepinephrine re-uptake inhibitor, including fluoxetine (PROZAC(trademark)), sertraline (ZOLOFT(trademark)), paroxetine (PAXIL(trademark)) and amitryptyline, for the treatment of depression, mood disorders or schizophrenia.
Additional features and advantages of the invention will become apparent from the detailed description and examples below, and the appended claims.
The present invention provides bicyclic compounds useful for the treatment of disorders and conditions modulated by a histamine receptor.
A. Terms
Certain terms are defined below and by their usage throughout this disclosure.
As used herein, xe2x80x9chalogenxe2x80x9d shall mean chlorine, bromine, fluorine and iodine, or monovalent radicals thereof.
As used herein, the term xe2x80x9calkylxe2x80x9d, whether used alone or as part of a substituent group, shall include straight and branched carbon chains. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like. Unless otherwise noted, xe2x80x9clowerxe2x80x9d when used with alkyl means a carbon chain composition of 1-4 carbon atoms. xe2x80x9cAlkylenexe2x80x9d refers to a bivalent hydrocarbyl group, such as methylene (CH2), ethylene (xe2x80x94CH2xe2x80x94CH2xe2x80x94) or propylene (xe2x80x94CH2CH2CH2xe2x80x94).
As used herein, unless otherwise noted, xe2x80x9calkoxyxe2x80x9d shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.
As used herein, unless otherwise noted, xe2x80x9ccycloalkylxe2x80x9d shall denote a three- to eight-membered, saturated monocyclic carbocyclic ring structure. Suitable examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
As used herein, unless otherwise noted, xe2x80x9ccycloalkenylxe2x80x9d shall denote a three- to eight-membered, partially unsaturated, monocyclic, carbocyclic ring structure, wherein the ring structure contains at least one double bond. Suitable examples include cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, cyclohex-1,3-dienyl and the like.
As used herein, unless otherwise noted, xe2x80x9carylxe2x80x9d shall refer to carbocyclic aromatic groups such as phenyl, naphthyl, and the like. Divalent radicals include phenylene (-C6H4-) which is preferably phen-1,4-diyl, but may also be phen-1,3-diyl.
As used herein, unless otherwise noted, xe2x80x9caralkylxe2x80x9d shall mean any alkyl group substituted with an aryl group such as phenyl, naphthyl and the like. Examples of aralkyls include benzyl, phenethyl, and phenylpropyl.
As used herein, unless otherwise noted, the terms xe2x80x9cheterocyclexe2x80x9d, xe2x80x9cheterocyclylxe2x80x9d and xe2x80x9cheterocycloxe2x80x9d shall denote any five-, six-, or seven-membered monocyclic, nine or ten membered bicyclic or thirteen or fourteen membered tricyclic ring structure containing at least one heteroatom moiety selected from the group consisting of N, O, SO, SO2, (C=O), and S, and preferably N, O, or S, optionally containing one to four additional heteroatoms in each ring. In some embodiments, the heterocyclyl contains between 1 and 3 or between 1 and 2 additional heteroatoms. Unless otherwise specified, a heterocyclyl may be saturated, partially unsaturated, aromatic or partially aromatic. The heterocyclyl group may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
Exemplary monocyclic heterocyclic groups can include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazaolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, hexahydroazepinyl, 4-piperidinyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dixolane and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl, triazolyl, tetrazolyl, azetidinyl and the like.
Exemplary bicyclic heterocyclic groups include benzthiazolyl, benzoxazolyl, benzoxazinyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl), or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl (such as 1,2,3,4-tetrahydroquinolinyl), tetrahydroisoquinolinyl(such as 1,2,3,4-tetrahydroisoquiunolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isoindolyl, tetrahydroindoazolyl (such as 4,5,6,7-tetrahydroindazolyl), isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl, 
and the like.
Exemplary tricyclic heterocylclic groups include acridinyl, phenoxazinyl, phenazinyl, phenothiazinyl, carbozolyl, perminidinyl, phenanthrolinyl, carbolinyl, naphthothienyl, thianthrenyl, and the like.
Preferred heterocyclyl groups include morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrimidinyl, pyridyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, acridinyl, azepinyl, hexahydroazepinyl, azetidinyl, indolyl, isoindolyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 1,3,4-trihydroisoquinolinyl, 4,5,6,7-tetrahydroindadolyl, benzoxazinyl, benzoaxzolyl, benzthiazolyl, benzimidazolyl, 
tetrazolyl, oxadiazolyl,
As used herein, unless otherwise noted, the term xe2x80x9cheterocyclyl-alkylxe2x80x9d or xe2x80x9cheterocyclyl-alkylenexe2x80x9d shall denote any alkyl group substituted with a heterocyclyl group, wherein the heterocycly-alkyl group is bound through the alkyl portion to the central part of the molecule. Suitable examples of heterocyclyl-alkyl groups include, but are not limited to piperidinylmethyl, pyrrolidinylmethyl, piperidinylethyl, piperazinylmethyl, pyrrolylbutyl, piperidinylisobutyl, pyridylmethyl, pyrimidylethyl, and the like.
When a particular group is xe2x80x9csubstitutedxe2x80x9d (e.g., alkyl, alkylene, cycloalkyl, aryl, heterocyclyl, heteroaryl), that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents.
It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.
Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a xe2x80x9cphenyl(alkyl)amido(alkyl)xe2x80x9d substituent refers to a group of the formula 
The term xe2x80x9csubjectxe2x80x9d as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes prevention, inhibition of onset, or alleviation of the symptoms of the disease or disorder being treated.
As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
Abbreviations used in the specification, particularly in the Schemes and Examples, are as follows:
The next section describes the compounds provided by the invention in more detail.
B. Compounds
The invention features compounds of formula (I) as described, for example, in the above Summary section and in the claims. Preferred compounds include those wherein:
(a) each of Ga and Gb is independently NR3aR4a or NR3bR4b, respectively, or pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, isoindolinyl, morpholinyl, piperazinyl, imidazolyl, thiazolinyl, 5,6-dihydro-3-imidazo[2,1-B]thiazolyl, or thiazolyl; wherein each of R3a, R4a, R3b and R4b is independently selected from H, C1-8 alkyl, C3-7 cycloalkyl, and (C3-7 cycloalkyl)C1-6 alkyl;
(b) wherein X, is LaGa;
(c) X2 is LbGb;
(d) X1 is LaGa and X2 is LbGb;
(e) X1 and X2 are independently selected from pyrrolidinylmethyl, piperidylmethyl, di(C1-2 alkyl)amino (C2-5 alkyl), and di(C1-2 alkyl)amino(C2-5 alkoxy);
(f) X1 is selected from Ga, RaGa, or RaLaGa;
(g) X2 is selected from Gb, RbGb, or RbLbGb;
(h) X1 and X2 are the same;
(i) each of Ga and Gb is independently NR3R4, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, isoindolinyl, morpholinyl, thiazolyl, thiazolinyl, 5,6-dihydro-3-imidazo[2,1-B]thiazolyl, or piperazinyl; where R3 and R4 are each independently selected from H and C1-4 alkyl;
(j) Y is O, S, SO2, Cxe2x95x90O, CH2, OCH2, CH2O, or NRc, wherein Rc is H, C1-8 alkyl, C3-7 cycloalkyl, (C3-7 cycloalkyl)C1-6 alkyl, C2-5 heterocyclyl, (C2-7 heterocyclyl)C1-6 alkyl, phenyl, (phenyl)C1-4 alkyl, or [di (C1-4 alkyl)amino]C1-6 alkyl; or
(k) combinations of the above.
The invention provides compounds such as: 1-[(4-(4-Pyrrolidin-1-ylmethyl-phenyl)-thiophen)-2-ylmethyl]-pyrrolidine; 1-[(4-(4-Pyrrolidin-1-ylmethyl-phenyl)-furan)-2-ylmethyl]-pyrrolidine; 1-((4-(4-Pyrrolidin-1-ylmethyl-thiophen)-2-ylthiophen)-2-ylmethyl)-pyrrolid ine; 1-[(2-(4-Pyrrolid in-1-ylmethyl-phenyl)-thiophen)-3-ylmethyl]-pyrrolidine; 1-[(3-(4-Pyrrolidin-1-ylmethyl-phenyl)-thiophen)-2-ylmethyl]-pyrrolidine; and 1-((4-(4-Pyrrolidin-1-ylmethyl-pyridin)-2-ylpyridin)-2-ylmethyl)-pyrrolidine.
Additional compounds of the invention include: 1-[4-(3,5-Dichloro-phenoxy)-benzyl]-pyrrolidine; 1-[4-(4-Piperidine-phenylsulfanyl)-3-nitro-benzyl]-piperidine; 4xe2x80x2-Pyrrolidin-1 -ylmethyl-biphenyl-4-carbaldehyde; 4xe2x80x2-Pyrrolidin-1-ylmethyl-biphenyl-4-carbaldehyde oxime; 3-Pyrrolid in-1-ylmethyl-1-(4-pyrrolid in-1-ylmethyl-benzyl)-1H-pyrrole; and 2-Pyrrolidin-1-ylmethyl-1-(4-pyrrolidin-1-ylmethyl-benzyl)-1H-pyrrole.
Further examples of compounds include: 1-[4-(4-Pyrrolidin-1-ylmethyl-phenoxy)-benzyl]-pyrrolidine; 1-[4-(4-Piperidin-1-ylmethyl-phenoxy)-benzyl]-piperidine; 1-[4-(4-Pyrrolidin-1-ylmethyl-benzenesulfonyl)-benzyl]-pyrrolidine; 1-[4-(4-Pyrrolidin-1-ylmethyl-benzyl)-benzyl]-pyrrolidine; 1-[4-(4-Imidazo-1-ylmethyl-phenoxy)-benzyl]-imidazole; 1-[4-(4-Imidazo-1-ylmethyl-benzyl)-benzyl]-imidazole; [4-(N, Nxe2x80x2-dimethyl-isothiourea)-methyl-phenoxy)-benzyl]-N, Nxe2x80x2-dimethyl-isothiourea; [4-(N-methyl-isothiourea)-methyl-phenoxy)-benzyl]-N-methyl-isothiourea; 2-[4-(4-(2-Imidazolidin)-2-ylthiomethyl-phenoxy)-benzyl-thio]-2-imidazolidine; 2-[4-(4-(2-Thiazolin)-2-ylthiomethyl-phenoxy)-benzyl-thio]-2-thiazoline; 2-[4-(4-(1-Methyl-imidazo)-2-ylthiomethyl-phenoxy)-benzyl-thio]-1-methyl-imidazole; 2-[4-(4-(2-Imidazolidin)-2-ylaminomethyl-phenoxy)-benzyl-amino]-2-imidazolidine and 1-(2-{4-[2-(1-phenethyl-pyrrolidine)-ethyl]-phenyl}-ethyl)-pyrrolidine.
Additional compounds include: (A) 1-[4-(4-Bromo-benzyloxy)-benzyl]-pyrrolidine; 1-[4-(4-Pyrrolidin-1-ylmethyl-phenoxymethyl)-benzyl]-1H-pyrrole; and 1-(4-Pyrrolidin-1-ylmethyl-benzyl)-1H-pyrrole; (B) Benzyl-(4-pyrrolid in-1-ylmethyl-phenyl)-amine; Benzyl-bis-(4-pyrrolidin-1-ylmethyl-phenyl)-amine; (3-Piperidin-1-yl-propyl)-bis-(4-pyrrolidin-1-ylmethyl-phenyl)-amine; and (2-(N,N-dimethylamine)ethyl)-bis-(4-pyrrolidin-1-ylmethyl-phenyl)-amine; and 3-[4-(4-(5,6-Dihydro-3-imidiazo[2,1-B]thiazol)-3-ylphenoxy)-phenyl]-(5,6-dihydro-3-imidiazo[2,1-B]thiazole); (D) Bis-[4-(3-dimethylamino-propylsulfanyl)-phenyl]-methanone dihydrochloride; Bis-[4-(3-dimethylamino-propoxy)-phenyl]-methanone; [4-(3-Dimethylamino-propoxy)-phenyl]-(4-hydroxy-phenyl)-methanone; and (E) Bis-[4-(2-dimethylamino-ethoxy)-phenyl]-methanone.
The invention also provides compounds that are useful as synthetic intermediates of the compounds of the invention. Such compounds, which themselves may or may not have pharmaceutical activity, include those provided in the schemes and synthetic examples.
The invention also contemplates compounds of the invention that have been isotopically modified to be detectable by positron emission tomography (PET) or single-photon emission computed tomography (SPECT), and methods of studying disorders mediated by the histamine H3 receptor, comprising using an 18F-labeled compound of claim 1 as a positron emission tomography (PET) molecular probe.
During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. In addition, compounds of the invention may be modified by using protecting groups; such compounds, precursors, or prodrugs are also within the scope of the invention. This may be achieved by means of conventional protecting groups, such as those described in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 3rd ed., John Wiley and Sons, 1999. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
Hydroxyl Protecting Groups
Protection for the hydroxyl group includes methyl ethers, substituted methyl ethers, substituted ethyl ethers, substitute benzyl ethers, and silyl ethers.
Substituted Methyl Ethers
Examples of substituted methyl ethers include methyoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl, guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S, S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperid in-4-yl, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.
Substituted Ethyl Ethers
Examples of substituted ethyl ethers include 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, and benzyl.
Substituted Benzyl Ethers
Examples of substituted benzyl ethers include p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p, pxe2x80x2-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, xcex1-naphthyldiphenylmethyl, p- methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4xe2x80x2-bromophenacyloxy)phenyidiphenylmethyl, 4,4xe2x80x2,4xe2x80x3-tris(4,5-dichlorophthalimidophenyl)methyl 4,4xe2x80x2,4xe2x80x3-tris(levulinoyloxyphenyl)methyl, 4,4xe2x80x2,4xe2x80x3-tris(benzoyloxyphenyl)methyl, 3-(lmidazol-1-ylmethyl)bis(4xe2x80x2,4xe2x80x3-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1xe2x80x2-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.
Silyl Ethers
Examples of silyl ethers include trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t-butyidimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and t-butylmethoxyphenylsilyl.
Esters
In addition to ethers, a hydroxyl group may be protected as an ester. Examples of esters include formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate, 4-oxopentanoate(levulinate), 4,4-(ethylenedithio)pentanoate, pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate(mesitoate)
Carbonates
Examples of carbonates include methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, 2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, and methyl dithiocarbonate.
Assisted Cleavage
Examples of assisted cleavage include 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate, 4-(methylthiomethoxy)butyrate, and 2-(methylthiomethoxymethyl)benzoate.
Miscellaneous Esters
Examples of miscellaneous esters include 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate), o-(methoxycarbonyl)benzoate, p-P-benzoate, xcex1-naphthoate, nitrate, alkyl N,N,Nxe2x80x2,Nxe2x80x2-tetramethylphosphorodiamidate, N-phenylcarbamate, borate, dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate
Sulfonates
Examples of sulfonates include sulfate, methanesulfonate(mesylate), benzylsulfonate, and tosylate.
PROTECTION FOR 1,2- AND 1,3-DIOLS
Cyclic Acetals and Ketals
Examples of cyclic acetals and ketals include methylene, ethylidene, 1-t-butylethylidene, I-phenylethylidene, (4-methoxyphenyl)ethylidene, 2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene, 2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and 2-nitrobenzylidene.
Cyclic Ortho Esters
Examples of cyclic ortho esters include methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1-ethoxyethylidine, 1,2-dimethoxyethylidene, xcex1-methoxybenzylidene, 1-(N, N-dimethylamino)ethylidene derivative, xcex1-(N,N-dimethylamino)benzylidene derivative, and 2-oxacyclopentylidene.
Silyl Derivatives
Examples of silyl derivatives include di-t-butylsilylene group, and 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivative.
AMINO PROTECTING GROUPS
Protection for the amino group includes carbamates, amides, and special-NH protective groups.
Examples of carbamates include methyl and ethyl carbamates, substituted ethyl carbamates, assisted cleavage carbamates, photolytic cleavage carbamates, urea-type derivatives, and miscellaneous carbamates.
Carbamates
Examples of methyl and ethyl carbamates include methyl and ethyl, 9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl, and 4-methoxyphenacyl.
Substituted Ethyl
Examples of substituted ethyl carbamates include 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl, 1,1-dimethyl-2-haloethyl, 1,1-dimethyl- 2,2- dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl, 1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2xe2x80x2- and 4xe2x80x2-pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl and diphenylmethyl.
Assisted Cleavage
Examples of assisted cleavage include 2-methylthioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, [2-(1,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1,1 -dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, and 2-(trifluoromethyl)-6-chromonylmethyl.
Photolytic Cleavage
Examples of photolytic cleavage include m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, and phenyl(o-nitrophenyl)methyl.
Urea-Type Derivatives
Examples of urea-type derivatives include phenothiazinyl-(10)-carbonyl derivative, Nxe2x80x2-p-toluenesulfonylaminocarbonyl, and Nxe2x80x2-phenylaminothiocarbonyl.
Miscellaneous Carbamates
Examples of miscellaneous carbamates include t-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl, isonicotinyl, p-(pxe2x80x2-methoxyphenylazo)benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl, 1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl, 1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl, 2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl, and 2,4,6-trimethylbenzyl.
Examples of amides include:
Amides
N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, N-benzoyl, N-p-phenylbenzoyl.
Assisted Cleavage
N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl, (Nxe2x80x2-dithiobenzyloxycarbonylamino)acetyl, N-3-(p-hydroxyphenyl)propionyl, N-3-(o-nitrophenyl)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl, N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl, N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethionine derivative, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, and 4,5-diphenyl-3-oxazolin-2-one.
Cyclic Imide Derivatives
N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl, N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, and 1-substituted 3,5-dinitro-4-pyridonyl.
SPECIALxe2x80x94NH PROTECTIVE GROUPS
Examples of special NH protective groups include:
N-Alkyl and N-Aryl Amines N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxy]methyl, N-3-acetoxypropyl, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salts, N-benzyl, N-4-methoxybenzyl, N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl, N-triphenylmethyl, N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl, N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, and N-2-picolylamine Nxe2x80x2-oxide.
Imine Derivatives
N-1,1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenzylidene, N-diphenylmethylene, N-[(2-pyridyl)mesityl]methylene, and N-(Nxe2x80x2,Nxe2x80x2-dimethylaminomethylene).
PROTECTION FOR THE CARBONYL GROUP
Acyclic Acetals and Ketals
Examples of acyclic acetals and ketals include dimethyl, bis(2,2,2-trichloroethyl), dibenzyl, bis(2-nitrobenzyl) and diacetyl.
Cyclic Acetals and Ketals
Examples of cyclic acetals and ketals include 1,3-dioxanes, 5-methylene-1,3-dioxane, 5,5-dibromo-1,3-dioxane, 5-(2-pyridyl)-1,3-dioxane, 1,3-dioxolanes, 4-bromomethyl-1,3-dioxolane, 4-(3-butenyl)-1,3-dioxolane, 4-phenyl-1,3-dioxolane, 4-(2-nitrophenyl)-1,3-dioxolane, 4,5-dimethoxymethyl-1,3-dioxolane, O,Oxe2x80x2-phenylenedioxy and 1,5-dihydro-3H-2,4-benzodioxepin.
Acyclic Dithio Acetals and Ketals
Examples of acyclic dithio acetals and ketals include S,Sxe2x80x2-dimethyl, S,Sxe2x80x2-diethyl, S,Sxe2x80x2-dipropyl, S,Sxe2x80x2-dibutyl, S,Sxe2x80x2-dipentyl, S,Sxe2x80x2-diphenyl, S,Sxe2x80x2-dibenzyl and S,Sxe2x80x2-diacetyl.
Cyclic Dithio Acetals and Ketals
Examples of cyclic dithio acetals and ketals include 1,3-dithiane, 1,3-dithiolane and 1,5-dihydro-3H-2,4-benzodithiepin.
Acyclic Monothio Acetals and Ketals
Examples of acyclic monothio acetals and ketals include O-trimethylsilyl-S-alkyl, O-methyl-S-alkyl or -S-phenyl and O-methyl-S-2-(methylthio)ethyl.
Cyclic Monothio Acetals and Ketals
Examples of cyclic monothio acetals and ketals include 1,3-oxathiolanes.
MISCELLANEOUS DERIVATIVES
O-Substituted Cyanohydrins
Examples of O-substituted cyanohydrins include O-acetyl, O-trimethylsilyl, O-1-ethoxyethyl and O-tetrahydropyranyl.
Substituted Hydrazones
Examples of substituted hydrazones include N,N-dimethyl and 2,4-dinitrophenyl.
Oxime Derivatives
Examples of oxime derivatives include O-methyl, O-benzyl and O-phenylthiomethyl.
Imines
Substituted Methylene Derivatives, Cyclic Derivatives
Examples of substituted methylene and cyclic derivatives include oxazolidines, 1-methyl-2-(1xe2x80x2-hydroxyalkyl)imidazoles, N,Nxe2x80x2-dimethylimidazolidines, 2,3-dihydro-1,3-benzothiazoles, diethylamine adducts, and methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide)(MAD)complex.
Monoprotection of Dicarbonyl Compounds
Selective Protection Of xcex1-and xcex2-Diketones
Examples of selective protection of xcex1-and xcex2-diketones include enamines, enol acetates, enol ethers, methyl, ethyl, i-butyl, piperidinyl, morpholinyl, 4-methyl-1,3-dioxolanyl, pyrrolidinyl, benzyl, S-butyl, and trimethylsilyl.
Cyclic Ketals, Monothio and Dithio Ketals
Examples of cyclic ketals, monothio and dithio ketals include bismethylenedioxy derivatives and tetramethylbismethylenedioxy derivatives.
Protection for the Carboxyl Group
Esters
Substituted Methyl Esters
Examples of substituted methyl esters include 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, phenacyl, p-bromophenacyl, xcex1-methylphenacyl, p-methoxyphenacyl, carboxamidomethyl, and N-phthalimidomethyl.
2-Substituted Ethyl Esters
Examples of 2-substituted ethyl esters include 2,2,2-trichloroethyl,
2-haloethyl, xcfx89-chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl, 1,3-dithianyl-2-methyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(p-toluenesulfonyl)ethyl,
2-(2xe2x80x2-pyridyl)ethyl, 2-(d iphenylphosphino)ethyl, 1-methyl-1-phenylethyl, t-butyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl, 4-(trimethylsilyl)-2-buten-1-yl, cinnamyl, xcex1-methylcinnamyl, phenyl, p-(methylmercapto)phenyl and benzyl.
Substituted Benzyl Esters
Examples of substituted benzyl esters include triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl, 5-dibenzosuberyl, 1-pyrenylmethyl, 2-(trifluoromethyl)-6-chromylmethyl, 2,4,6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl, 4-picolyl and p-P-benzyl.
Silyl Esters
Examples of silyl esters include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, i-propyidimethylsilyl, phenyidimethylsilyl and di-t-butylmethylsilyl.
Activated Esters
Examples of activated esters include thiols.
Miscellaneous Derivatives
Examples of miscellaneous derivatives include oxazoles, 2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines, 5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group and pentaaminocobalt(III) complex.
Stannyl Esters
Examples of stannyl esters include triethylstannyl and tri-n-butylstannyl.
AMIDES AND HYDRAZIDES
Amides
Examples of amides include N,N-dimethyl, pyrrolidinyl, piperidinyl, 5,6-dihydrophenanthridinyl, o-nitroanilides, N-7-nitroindolyl, N-8-Nitro-1,2,3,4-tetrahydroquinolyl, and p-P-benzenesulfonamides.
Hydrazides
Examples of hydrazides include N-phenyl and N,Nxe2x80x2-diisopropyl.
The compounds of the invention can be prepared according to the methods described in the next section.
C. Synthesis
The compounds of the invention can be prepared according to traditional synthetic organic methods and matrix or combinatorial chemistry methods, as shown in Schemes 1-7 below and in Examples 1-34. A person of ordinary skill will be aware of variations and adaptations of the schemes and examples provided to achieve the compounds of the invention. One skilled in the art will recognize that synthesis of the compounds of the present invention may be effected by purchasing intermediate or protected intermediate compounds described in any of the schemes disclosed herein.
Compounds of formula I may be prepared according to the processes outlined in Schemes 1 through 5.
Compounds of formula V and formula VII, wherein the substituents are as defined in formula I, may be prepared according to the process outlined in Scheme 1. Specifically compounds of formula II and formula III react to provide a compound of formula IV in Step A upon treatment with Pd catalyst such as Pd2(dba)3, a ligand such as triphenylphosphine, or t-tributylphosphine, in presence of a base, for example cesium carbonate, potassium carbonate or the like in a solvent such as dioxane, or THF. In a preferred embodiment the compounds of formula II and III react in presence of Pd2(dba)3, t-tributylphosphine, cesium carbonate in dioxane to afford a compound of formula IV. In Step B a compound of formula IV upon treatment with an appropriately Ga-H, where Ga is the defined substituents Ga in formula I, in the presence of a reductant such as NaBH4, or NaB(OAc)3H in acidic condition, for example HOAc, in methylene chloride provides a compound of formula V. In a preferred embodiment the reductant is NaB(OAc)3H.
A compound of formula VI may be obtained, in Step C, by reacting a compound of formula IV with an appropriately amount of Ga-H, where Ga is the defined substituents Ga in formula I. The reaction condition is same as that of for a compound of formula V except the amount of Ga-H is a half of that for a compound of formula V.
A compound of formula VII may be obtained, in Step D, by treating a compound of formula of VI with Gb-H where Gb is the defined substituents Gb in formula I, in the presence of a reductant such as NaBH4 or NaB(OAc)3H in acidic condition, for example in HOAc, in methylene chloride. A compound of formula VII may also be obtained, in Step D, by treating hydroxyamine, or alkylated hydroxyamine, in presence of a base such as cesium carbonate, potassium carbonate, sodium carbonate or the like in a solvent such as methanol, or ethanol. In a preferred embodiment a compound of formula VI is treated with hydroxyamine, and sodium carbonate in ethanol to afford a compound of formula VII. 
Compounds of formula X and formula XII, wherein the substituents are as defined in formula I, may be prepared according to the process outlined in Scheme 2. Specifically a compound of formula VIII is converted to a compound of formula IX in Step E upon treatment with thionyl chloride, or oxalyl chloride in chloroform, dichloromethane, or dichloroethane at room temperature or an elevated temperature. In a preferred embodiment the compounds of formula VIII reacts with thionyl chloride in chloroform at 50-70xc2x0 C. providing a compound of formula IX. In Step F a compound of formula IX upon treatment with an appropriately Ga-H, where Ga is the defined substituents Ga in formula 1, in the presence of a base, for example cesium carbonate, potassium carbonate, sodium carbonate or the like in a solvent such as acetone, or acetonitrile provides a compound of formula X. In a preferred embodiment, the base is potassium carbonate and the solvent is acetonitrile.
A compound of formula of IX in Step G reacts with phthalimide, in presence of a base, for example cesium carbonate, potassium carbonate, sodium carbonate or the like in DMF to afford an intermediate. In a preferred embodiment the base is potassium carbonate. The intermediate may react with hydrazine in a mixture of methanol and THF at elevated temperature preferably at the boiling point of the mixed solvents providing a compound of formula XI.
A compound of formula XI is converted to a compound of formula XII in Step H upon treatment with an appropriately isothiourea, or alkylated isothiourea in pyridine at reflux temperature. In a preferred embodiment the compound of formula XI reacts with 2-thio-2-imidazoline in pyridine at reflux providing a compound of formula IX. 
Compounds of formula XV and formula XVIII, wherein the substituents are as defined in formula I, may be prepared according to the process outlined in Scheme 3. Specifically a compound of formula XIII is converted to a compound of formula XV in Step I by reacting with a compound of formula XIV in the presence of a base, for example sodium t-butoxide, potasium t-butoxide, cesium carbonate, potassium carbonate, sodium carbonate or the like in a solvent such as methanol, or ethanol. In a preferred embodiment, the base is t-butoxide and the solvent is ethanol.
A compound of formula of XIII in Step J reacts with a compound of formula of XVI, wherein Z2 is nitrogen, in presence of tetrabutylammonium hydrogen sulfate, and a base for example cesium carbonate, potassium carbonate, or sodium hydroxide in a solvent such as benzene, or toluene to afford a compound of formula of XVII. In a preferred embodiment the base is sodium hydroxide, and the solvent is benzene.
A compound of formula XVIII may be obtained in Step K by treating a compound of formula XVII with an appropriately Ga-H, where Ga is the defined substituents Ga in formula I, in the presence of a reductant such as NaBH4, or NaB(OAc)3H in acidic condition, for example HOAc, in methylene chloride. In a preferred embodiment the reductant is NaB(OAc)3H. 
Compounds of formula XX wherein the substituents are as defined in formula I, may be prepared according to the process outlined in Scheme 4. Specifically a compound of formula XIX is converted to a compound of formula XX in step L upon treatment with amine NHRC, which is RC is the defined substituents RC in compounds of formula I, Pd catalyst such as Pd2(dba)3, a ligand such as triphenylphosphine, or t-tributylphosphine, in presence of a base, for example cesium carbonate, potassium carbonate, or the like in a solvent such as dioxane, or THF. In a preferred embodiment the compound of formula XIX reacts with amine NHRC in the presence of Pd2(dba)3, t-tributylphosphine, cesium carbonate in dioxane to afford a compound of formula XX. 
A compound of formula XXI in Step M is treated with an appropriately thiourea, or alkylated thiourea, in a solvent such as methanol or ethanol at reflux temperature for certain time like 1 or 2 hour. Subsequently a base such as triethylamine, cesium carbonate, potassium carbonate, or the like was treated providing a compound of formula XXII. In a preferred embodiment the compound of formula XXI reacts with 2-imidazolidinethione in ethanol at reflux followed by treating triethylamine to afford a compound of formula XXII. 
A compound of formula XXIII in Step N is treated with an appropriately dialkylamino-alkyl-thiol and a base such as sodium hydride in the presence of a catalyst such as Pd(PPh3)4 in a solvent such as n-butanol at reflux temperature for a certain time like 6 hours providing a compound of formula XXIV. 
A compound of formula XXV in Step O is treated with an appropriately dialkylamino-alkyl-halogen and a base such as potasium t-butoxide in a solvent such as methanol or ethanol at reflux temperature for a certain time like 18 or 24 hours providing a compound of formula XXVI.
D. Formulation, Administration, and Therapy
The disclosed compounds, alone or in combination (with, for example, a histamine H1 receptor antagonist), are useful for treating or preventing neurologic disorders including sleep/wake and arousal/vigilance disorders (e.g. insomnia and jet lag), attention deficit hyperactivity disorders (ADHD), learning and memory disorders, cognitive dysfunction, migraine, neurogenic inflammation, dementia, mild cognitive impairment (pre-dementia), Alzheimer""s disease, epilepsy, narcolepsy, eating disorders, obesity, motion sickness, vertigo, schizophrenia, substance abuse, bipolar disorders, manic disorders and depression, as well as other histamine H3 receptor mediated disorders such as upper airway allergic response, asthma, itch, nasal congestion and allergic rhinitis in a subject in need thereof.
1. Formulation and Administration
The compounds or compositions of the invention may be formulated and administered to a subject by any conventional route of administration, including, but not limited to, intravenous, oral, subcutaneous, intramuscular, intradermal and parenteral administration. The quantity of the compound which is effective for treating each condition may vary, and can be determined by one of ordinary skill in the art.
For use in medicine, the salts of the compounds of this invention refer to non-toxic xe2x80x9cpharmaceutically acceptable salts.xe2x80x9d Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali ml salts, e.g., sodium or potassium salts; alkaline earth ml salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
Thus, representative pharmaceutically acceptable salts include the following:
acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term xe2x80x9cadministeringxe2x80x9d shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preption of suitable prodrug derivatives are described, for example, in xe2x80x9cDesign of Prodrugsxe2x80x9d, ed. H. Bundgaard, Elsevier, 1985. In addition to salts, the invention provides the esters, amides, and other protected or derivatized forms of the described compounds.
Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
The present invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier and optionally additional pharmaceutical agents such as H1 antagonists or SSRIs. Preferably these compositions are in unit dosage forms such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), powders, granules, sterile parenteral solutions or suspensions (including syrups and emulsions), metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules.
This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 5 to about 1000 mg of the active ingredient of the present invention. Examples include 5 mg, 7 mg, 10 mg, 15 mg, 20 mg, 35 mg, 50 mg, 75 mg, 100 mg, 120 mg, 150 mg, and so on. The tablets or pills of the disclosed compositions can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be septed by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the compounds and compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (xe2x88x92)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
The compound of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phophatidylcholines.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residue. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of ADHD is required.
The daily dosage of the products may be varied over a wide range from 1 to 1,000 mg per adult human per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 20 mg/kg of body weight per day. Preferably, the range is from about 0.02 mg/kg to about 10 mg/kg of body weight per day, and especially from about 0.05 mg/kg to about 10 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 4 times per day.
Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
2. Combination Therapy
The disclosed compounds are useful in combination with other therapeutic agents, including H1 receptor antagonists, H2 receptor antagonists, and neurotransmitter modulators such as SSRIs and non-selective serotonin re-uptake inhibitors (NSSRIs).
Methods are known in the art for determining effective doses for therapeutic and prophylactic purposes for the disclosed pharmaceutical compositions or the disclosed drug combinations, whether or not formulated in the same composition.
For therapeutic purposes, the term xe2x80x9cjointly effective amountxe2x80x9d as used herein, means that amount of each active compound or pharmaceutical agent, alone or in combination, that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. For prophylactic purposes (i.e., inhibiting the onset or progression of a disorder), the term xe2x80x9cjointly effective amountxe2x80x9d refers to that amount of each active compound or pharmaceutical agent, alone or in combination, that inhibits in a subject the onset or progression of a disorder as being sought by a researcher, veterinarian, medical doctor or other clinician, the delaying of which disorder is mediated, at least in part, by the modulation of one or more histamine receptors. Thus, the present invention provides combinations of two or more drugs wherein, for example, (a) each drug is administered in an independently therapeutically or prophylactically effective amount; (b) at least one drug in the combination is administered in an amount that is sub-therapeutic or sub-prophylactic if administered alone, but is therapeutic or prophylactic when administered in combination with the second or additional drugs according to the invention; or (c) both drugs are administered in an amount that is sub-therapeutic or sub-prophylactic if administered alone, but are therapeutic or prophylactic when administered together. Combinations of three or more drugs are analogously possible. Methods of combination therapy include co-administration of a single formulation containing all active agents; essentially contemporaneous administration of more than one formulation; and administration of two or more active agents separately formulated.